Epigenetic silencing of TET1 mediated hydroxymethylation of base excision repair pathway during lung carcinogenesis☆
Graphical abstract
Introduction
Lung cancer has been the most common cancer and the leading cause of cancer-related death among all patients worldwide (Siegel et al., 2020). Epidemiological studies have found that more than 80% of human lung cancers are closely related to human exposure to chemical carcinogens in living and working environments (He et al., 1991; Venkatesh et al., 2015). In recent years, the important role of epigenetic regulation in chemical carcinogenesis has been gradually discovered and confirmed (Belinsky et al., 2015). Studies have shown that DNA methylation not only helps to elucidate the mechanism of chemical carcinogenesis, but also can be used as an epigenetic biomarker for early diagnosis and prevention of cancer, screening of susceptible populations and assessment of carcinogenic risk of environmental exposure (Cavalli et al., 2019; Feil et al., 2012; Ladd-Acosta et al., 2016; Li et al., 2014).
DNA methylation is mainly 5-methylcytosine (5-mC), which strictly regulates gene expression in a dynamic equilibrium by DNMT1, DNMT3a, and DNMT3b in higher eukaryotic cells (Huang et al., 2014). Recent studies have found Ten-eleven translocation (TET) family can catalyze the conversion of 5-mC to 5-hydroxymethylcytosine (5-hmC), then thus regulated the balance of DNA methylation (Melamed et al., 2018). TET1 and 5-hmC levels are significantly correlated with the occurrence, development and prognosis of human solid tumors (Wu et al., 2019a). However, the regulatory mechanism of TET1 gene and 5-hmC in lung cancer is still unknown.
TET1 protein could oxidize 5 hmC to 5-carboxylcytosine, and that glycosidase TDG could specifically recognize and remove 5-carboxylcytosine from DNA, and then initiate base excision repair (BER) pathway to complete DNA demethylation (Melamed et al., 2018). OGG1, APEX1 and XRCC1 genes are mainly responsible for the process of removing damaged bases, producing single strand breaks and repairing and closing after base excision (Carter et al., 2016; Wallace et al., 2014). Reduced expression or functional deficiency of any of these genes may affect the efficiency of repairing DNA damage, lead to damage and increase the susceptibility of tumors. TET1-mediated demethylation requires the involvement of BER pathway in embryonic stem cells (Okashita et al., 2014). Inhibitor treatment of the key genes APEX1 and PARP1 of the BER pathway, or knockdown of TDG expression can block the demethylation process (Müller et al., 2014). However, it remains unclear how TET1 regulates the coordination of BER pathway and participates in demethylation process in lung carcinogenesis. In this study, we explored the epigenetic regulation, function and mechanism of TET1 gene and BER pathway during lung carcinogenesis.
Section snippets
Cell culture and malignant transformation model
The human bronchial epithelial cell line HBE and lung cancer cell lines A549, SPC-A-1, LTEP-a-2, NCI–H520, NCI–H460, NCI–H1975, NCI–H358 and 95D were purchased from the cell bank of the Type Culture Collection of the Chinese Academy of Sciences (Shanghai, China) and the American Type Culture Collection (ATCC, USA). HBE cells were cultured in DMEM medium (high-glucose) containing 10% fetal bovine serum (Gibco, USA) at 5% CO2 and 37 °C, and other cells were cultured in RPMI-1640 medium containing
TET1 expression was down-regulated during 3-MCA induced lung carcinogenesis and human tumor samples
Firstly, in order to detect the expression of TET1 gene during the process of chemical-induced lung carcinogenesis, TET1 expression of the 3-MCA-induced malignant transformation in HBE cell was detected by qRT-PCR (Fig. 1A) and Western blot (Fig. 1B). With the increase of 3-MCA treatment time, the mRNA and protein expression of TET1 gene gradually decreased significantly (P < 0.01). Then, qRT-PCR and Western blot was used to detect TET1 gene expression in the lung tissues of the 3-MCA-exposed
Discussion
Accumulating evidence has discovered that TET1 played important roles in the occurrence and development of neoplastic diseases (Su et al., 2019; Wu et al., 2019b). It has reported that overexpression of TET1 could significantly inhibit cell growth, migration and invasion of colon cancer and cervical cancer (Guo et al., 2019; Neri et al., 2014; Su et al., 2019). In addition, the recent study also found that TET1 involved in p53 mediated lung cancer cellular aging as an oncogene (Filipczak
Conclusion
We clarified for the first time that TET1 down-regulated associated with DNA methylation and acted as a novel tumor suppressor that inhibited cell growth and metastasis through BER pathway in lung cancer. TET1 regulated the level of hydroxymethylation and methylation in the promoter region of key genes in BER pathway, which participates in the whole process of lung cancer induced by environmental chemicals. Our study is not only of great significance to elucidate the pathogenesis of chemical
Author statement
Hong-qiang Chen: Conceptualization, Methodology, Data curation, Writing - original draft preparation, Investigation, and Validation. Dong-jiao Chen: Investigation, and Validation. Yan Li: Investigation, and Validation. Wen-bo Yuan: Investigation, and Validation. Jun Fan: Investigation, and Validation. Zhe Zhang: Investigation, and Validation. Fei Han: Investigation. Xiang Jiang: Investigation. Jian-ping Chen: Investigation. Dan-dan Wang: Investigation. Jia Cao: Supervision, Writing- Reviewing.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
This work was supported by grants from the National Natural Science Foundation of China (No. 81573114 and 81872659) and the Natural Science Foundation Project of Chongqing CSTC of China (No. cstc2018jcyjAX0233).
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This paper has been recommended for acceptance by Wen Chen.